The relentless rise in melanoma incidence provides an opportunity to reevaluate our understanding of its etiology. This proposal represents a longstanding funded project on the MITF transcription factor, whose master regulatory role in melanocyte development was elucidated largely through this NIH-funded research. Among many discoveries are 1) the central role of MITF as a dysregulated oncogene (via amplification or point mutation) and 2) MITF's key role regulating pigmentation, one of the most important predictors of melanoma risk. MITF expression is regulated by MC1R, a receptor whose nonfunctional variants produce the redhair/fairskin phenotype- conferring the highest melanoma risk of any pigment background in man. Here we report a new observation involving BRAF(V600E) melanoma-genesis. In black mice, BRAF(V600E) requires a second hit to produce highly penetrant melanoma (eg PTEN loss). However we observed that in redheads, BRAF(V600E) produced highly penetrant invasive melanomas after brief latency, without providing a second engineered cancer allele. This melanoma-prone behavior of redhead mice occurred without UV exposure. Consequently fairskin melanoma risk in redheads is at least partially independent of UV shielding. Furthermore incorporation of an albino allele (ablating all pigment, but leaving melanocytes otherwise intact) rescued the redhead (white-redhead) mice from elevated melanoma risk. Thus the red/blond pigment pathway is a UV-independent melanoma carcinogen, and our animal model provides a robust, tractable system in which to elucidate its mechanistic basis. In Aim 1 we will examine ROS as potential mediator of pheomelanin carcinogenesis by studying combinations of in vivo, in vitro, deep genome, and mass spec approaches (collaborating with experts in these technologies). We will also study prevention strategies: anti-oxidants and topicals switching skin pigmentation. Aim 2 investigates a putative melanoma oncogene, PDE4D-IP, amplified in 25% of melanomas, and predicted to disrupt cAMP homeostasis, thereby producing a novel oncogenic mechanism of MITF dysregulation. Aim 3 examines our discovery of a discrete class of MITF transcriptional targets: REDOX related factors. We believe they function during MITF-induced pigmentation to protect against ROS, including ROS-induced carcinogenesis. Collectively we extend our deep analyses of MITF biology into a translational direction that relates melanocytic homeostasis to melanomagenesis and novel prevention strategies. !